During development, cells and molecules of the central nervous system (CNS) execute an astonishingly intricate function to culminate in the precise localization of neurons wired in a functional networked circuitry. In my lab, we seek to understand aspects of this process, particularly those which persist into adulthood and may at times be co-opted into disease processes.

In particular, my lab studies adhesion G protein-coupled receptors (aGPCRs) and their extracellular matrix (ECM) partners. Our goal is to decode how cell-cell and cell-ECM interactions contribute both to development and disease. The aGPCRs are remarkably well-suited to this research strategy: individual members interact with multiple binding partners and are indispensable for formation of the blood-brain barrier (BBB); the myelin of peripheral nerves; and for synaptic refinement in the postnatal cortex.

While we investigate several aGPCRs, GPR56 serves as an exemplary prototype of our “bedside to bench to bedside” paradigm. My interest in aGPCRs stemmed from my postdoctoral work in Christopher Walsh’s lab at Harvard Medical School where I used a genetic approach to study human brain development and discovered mutant GPR56 as a cause of neurodevelopmental disease. The GPR56-associated neurodevelopmental disease, bilateral frontoparietal polymicrogyria (BFPP), results from universal (germline) lack of GPR56 at a specific point in brain development, due to homozygosity of any of several function-null mutants. In more than 10 years since then, we’ve discovered that GPR56 is highly expressed in several brain cell types including neural progenitor cells, oligodendrocytes, astrocytes, and microglia. The GPR56 gene is formidably complex, harboring multiple transcriptional start sites, differential splicing, post-translational processing and yet-to-be discovered ligands. Motivated by finding distinct phenotypes for selective loss of GPR56 function in individual brain-cell types we’ve taken GPR56 into model systems to clarify its pleiotropic and cell-type-specific functions in development. We look forward eagerly to deciphering aGPCR function and signaling at a level that will enable therapeutic targeting.

The first major line of ongoing research focuses on characterizing GPR56 and its binding partners in oligodendrocyte development and CNS myelination during development. The disease association here is the process of myelin repair (remyelination), the only robust neuroregenerative mechanism that operates in the adult human brain. Oligodendrocytes are the main source of myelin in the CNS and myelinate by extending their processes and repeatedly wrapping them around the axons, allowing both for trophic support of nerve fibers and rapid signal transduction down the axons. Our research previously showed that GPR56 plays an important role in the proliferation of oligodendrocyte precursor cells. We are now working on identifying the ligands of GPR56 present during myelination. Further, we are investigating the interactions between different glial cells mediated by GPR56 and their binding partners on CNS remyelination. Importantly, remyelination may be relevant for disease beyond the evident myelin disorders such as multiple sclerosis (MS). For example, prominent white matter degeneration is also characteristic of early Alzheimer disease (AD). We pursue the mechanisms by which oligodendroglial GPR56 and its ligands contribute to myelin formation and repair, mindful of the potential of this research to contribute to therapeutic strategies.

Our second line of research is to study the role of microglial GPR56 in the development and function of the brain. Originating from the primitive myeloid cells in the yolk sac, microglia are tissue-resident macrophages in the CNS and enter the brain at the start of brain development. First described in the early years of the twentieth century, microglia have long been considered innate immune cells that primarily serve to clear injured/dead cells and infectious agents from the CNS. However, what we now know is that microglial physiology is dominated by physiological roles during neurodevelopment and synapse maintenance in the adult CNS. The pathological contributions of microglia to neurological disorders relate more closely to loss of physiological function than to gain of inflammatory toxicity. Tantalizingly, GPR56 is highly expressed in the microglia of the postnatal brain with currently unknown function. Our work will shed light on the molecular mechanisms underlying microglia-mediated brain development.